Most theories of nervous system function depend heavily on the properties of the synapse and for this reason the synapse has been a focus of neuroscience research for many decades. The synapse is also the focus of medical and pharmaceutical research because in general the drugs which have proven useful for the treatment of mental illness and neurological disease act on various aspects of synaptic function, i.e. transmitter uptake and metabolism, ion channels and receptors. It is also likely that synaptic changes underlie the long term or permanent changes that take place in memory formation and learning. Recently there are suggestions that similar long-term changes in synaptic transmission take place as part of the mechanism of many neurological diseases such as epilepsy, drug addiction and long term intractable pain. Long-term alterations in synaptic function may explain the symptoms of withdrawal experienced by addicts when drug administration is terminated. Little is known about the function of the kainate receptor subtype of the glutamate receptor family which is a major focus of this grant application made possible by the recent cloning of the kainate receptor genes. Using genetically engineered mice it has recently been shown that kainate receptors regulate synaptic transmission and synaptic plasticity. Thus, they play a critical role in the brain and kainite receptor miss function may underlie many pathological conditions that affect the brain. The role of kainite receptors will be studied making use of a battery of mutant mice, which have or will be engineered to alter the kainate receptor system and synaptic transmission. A search for glutamate receptor modulatory and accessory proteins will be undertaken using a new proteomic approach. Behavioral studies will be conducted to elucidate the role of kainate receptors in the hippocampus in memory and learning. Results from these studies will provide insight into the role that specific glutamate receptor subtypes play in the nervous system The results and insights from these studies should make it possible to use recombinant DNA technology and high throughput screening to develop new drugs to treat epilepsy, pain, stroke, mental illness, degenerative diseases and drug addiction.